Copper-64 has applications for positron emission tomography (PET) imaging and targeted radiotherapy of cancer. One of the goals of this SBIR is to study two novel 64Cu-labeled phosphonate macrocyclic complexes for their uptake in normal bone. A second goal of this proposal is to demonstrate the potential of the lead compound, 64Cu-DO3P (1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid)), as a radiopharmaceutical for bone imaging using positron emission tomography (PET) and therapy for bone metastases. Our hypothesis is that 64Cu-labeled macrocyclic complexes containing phosphonate groups will adhere to normal bone and bone metastases and imaging and therapy will be accomplished with the same agent. The advantage of this class of agents for bone metastasis therapy is that dosimetry with the same agent will be determined with PET prior to therapy. We will evaluate, by microPET imaging, 64Cu-DO3P in two mouse models of bone metastases using the same cell line (B 16F10 mouse melanoma tumor cells). Therapeutic studies will be performed in one of the metastasis models to determine if higher doses of 64Cu-DO3P will ablate the bone tumors. Our Specific Aims are as follows: l. To synthesize sufficient amounts (up to 1g) of the methanephosponate derivative DO3A-P and the bisphosphonate amide derivative DO3A-BPA. We will develop an HPLC method for DO3P, DO3A-P and DO3A-BPA, and the copper complexes of these ligands to establish purity levels. 2. To perform microPET imaging studies on 64Cu-DO3P in an osteolytic melanoma bone metastasis model to see the progression of tumors to the skeleton over the course of tumor growth. 3. To evaluate 64Cu-labeled complexes from Aim 1 for their in vivo stability and bone uptake compared to the lead compound, 64Cu-DO3P. If either 64Cu-DO3A-P or 64Cu-DO3A-BPA has greater uptake in bone and more optimal clearance than 64Cu-DO3P, then that agent will undergo further investigation in PET imaging studies in the bone metastasis model. 4. To perform preliminary experiments to investigate if 64Cu-DO3P, or the most optimal 64Cu complex determined from Aim 3, has therapeutic efficacy in two mouse bone metastasis model compared to unlabeled Cu-DO3P and uncomplexed DO3P.